Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Shire Services BVBA, Rue Montoyer 47, B-1000, Brussels, Belgium
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Thrombotic events have been reported in neonatal and infant subjects undergoing cardiac bypass procedures while receiving off-label high doses of another C1 inhibitor product (up to 500 Units()/kg) to prevent capillary leak syndrome. Based upon an animal study there is a potential thrombogenic threshold at doses greater than 200 Units()/kg. Patients with known risk factors for thrombotic events (including indwelling catheters) should be monitored closely.
(*) [Historically assigned potency values were relative to an in-house reference standard whereby 1 Unit (U) is equal to the mean quantity of C1 inhibitor present in 1 ml of normal human plasma.] An international reference standard (IU) has now been implemented where IU is also defined as the amount of C1 inhibitor present in 1 ml of normal human plasma.
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19.
Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived C1 inhibitor product.
It is strongly recommended that every time Cinryze is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.
As with any biological product hypersensitivity reactions may occur. Hypersensitivity reactions may have symptoms similar to angioedema attacks. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur after administration, they should alert their physician. In case of anaphylactic reactions or shock, emergency medical treatment should be administered.
There are limited data on the use of this medicinal product in home- or self administration. Potential risks associated with home-treatment are related to the administration itself as well as the handling of adverse reactions, particularly hypersensitivity. The decision on the use of home- treatment for an individual patient should be made by the treating physician, who should ensure that appropriate training is provided and the use reviewed at intervals.
Thrombotic events have been reported in neonatal and infant subjects undergoing cardiac bypass procedures while receiving off-label high doses of another C1 inhibitor product (up to 500 Units(*)/kg) to prevent capillary leak syndrome.
Each vial of Cinryze contains approximately 11.5 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.
No interaction studies have been performed.
Data on a limited number of exposed pregnancies indicate no adverse effects of C1 inhibitor on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. No maternal or embryofoetal effects of treatment were observed in reproductive studies in rats at dose levels up to 28-times the recommended human dose (1000 IU) based on an average adult body weight of 70 kg. The potential risk for humans is unknown.
Therefore, Cinryze should be given to pregnant women only if clearly indicated.
It is unknown whether C1 inhibitor is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Cinryze therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
No specific studies on fertility, early embryonic and postnatal development, or carcinogenicity studies were conducted (see section 5.3).
Based upon the clinical data currently available, Cinryze has minor influence on the ability to drive and use machines.
The very common adverse reactions observed following Cinryze infusion in clinical studies were headache and nausea.
Adverse reaction frequencies were estimated from 2 pivotal placebo-controlled and 2 open-label studies in 251 unique subjects. Only frequencies based on reporting rates from clinical trials are used to assign frequency category.
Adverse reactions to treatment with Cinryze are classified by MedDRA System Organ Class and absolute frequency in Table 1. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).
Table 1. Adverse reactions reported in clinical studies and in postmarketing reports:
Common: Hypersensitivity
Uncommon: Hyperglycaemia
Very common: headache
Common: Dizziness
Uncommon: Venous thrombosis, phlebitis, venous burning, hot flush
Uncommon: Cough
Very common: Nausea
Common: vomiting
Uncommon: Diarrhoea, abdominal pain
Common: Rash, erythema, pruritus
Uncommon: Contact dermatitis
Uncommon: Joint swelling, arthralgia, myalgia
Common: Injection site rash/erythema, infusion site pain, pyrexia
Uncommon: Chest discomfort
Among reports of venous thrombosis, the most common underlying risk factor was presence of an indwelling catheter.
Local reactions at the injection site were uncommon. In clinical studies local reactions (described as pain, bruising, or rash at the injection/catheter site, venous burning or phlebitis) occurred in association with approximately 0.2% of infusions.
Across clinical studies, there were 61 unique paediatric subjects enrolled and exposed to over 2,500 infusions of Cinryze (2-5 years, n=3; 6-11 years, n=32; 12-17 years, n=26). Among these children, the only adverse reactions with Cinryze included headache, nausea, pyrexia, and infusion site erythema. None of these adverse reactions were severe, and none led to discontinuation of medicinal product.
Overall, the safety and tolerability of Cinryze are similar in children, adolescents and adults.
For safety with respect to transmissible agents, see section 4.4.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
United Kingdom, Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Ireland: HPRA Pharmacovigilance, Website: www.hpra.ie.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Only use a silicone-free syringe (provided in the pack) for administration of the product.
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